Building a Systems-Level View of Cell Cycle Checkpoints

构建细胞周期检查点的系统级视图

• 批准号: 7571659
• 负责人: JILL C SIBLE
• 金额: $ 22.22万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-06 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571659
• 关键词: Address; Affect; Agreement; Area; Behavior; Biochemical; Biological Models; Biology; Cell Cycle; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Cycle Regulation; Cell Nucleus; Cell Proliferation; Cells; Cellular biology; Checkpoint kinase 1; Collaborations; Complex; Cyclins; DNA; DNA biosynthesis; Data; Development; Disease; Embryo; Environment; Enzymes; Eukaryota; Eukaryotic Cell; Event; Foundations; Genome; Genome Stability; Genomics; Goals; Growth and Development function; Hand; Internet; Intervention; Knowledge; Malignant Neoplasms; Maturation-Promoting Factor; Measures; Mitosis; Mitotic; Modeling; Modification; Molecular; Mutation; Nuclear; Pathologic; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Problem Solving; Process; Rana; Relative (related person); Reproduction; Research Personnel; Signal Pathway; Somatic Cell; System; Testing; Therapeutic Intervention; Time; Work; Xenopus; Xenopus laevis; cancer cell; design; egg; embryo cell; forging; mathematical model; novel; research study; response; theories; tool

Because the cell cycle underlies the growth and development of all eukaryotes, and misregulation of the cell cycle typifies cancers, achieving a systems-level understanding of how the cell cycle is controlled ranks among the most important goals in modern cell biology. Pairing experimental biology with mathematical modeling in a highly interactive collaboration creates a powerful approach to develop a comprehensive understanding of cell cycle control. This approach was used to discover that mitotic transitions are regulated by hysteresis and bistability. The next goal is to build on this foundation by addressing a critical issue: how the cell cycle engine is affected by external events, in particular, those events that threaten the integrity of the genome. Checkpoints arrest the cell cycle when a threat to genomic stability, such as unreplicated or damaged DMA, exists. Loss of checkpoint control characterizes nearly all cancer cells. Checkpoints will be investigated in the experimentally tractable cell-free extracts derived from eggs of Xenopus laevis and in Xenopus embryos, where the cell cycle extensively remodels during early development. To build this understanding, a mathematical model of the DNA replication checkpoint will be constructed and subjected to rigorous experimental testing. This model should reveal underlying dynamical controls and serve as a powerful tool for predicting the effect of pathologic and pharmacologic perturbations upon cell cycle checkpoints. To reach the goal of constructing a systems-level view of the DNA replication checkpoint, the following specific aims will be completed: 1) A mathematical model representing the effect of unreplicated DNA on the core cell cycle engine will be constructed, parameters will be optimized, and the model will be made available for public use on the World Wide Web. 2) Concurrently, key quantitative experiments concerning how nuclear concentration and cell cycle enzymes impact the DNA replication checkpoint will be conducted and data used to inform the model. 3) Once this fundamental view of how unreplicated DNA affects the cell cycle engine is in hand, the model will be extended to include the Chk1 kinase signaling pathway, a key potential target for cancer chemotherapeutics. 4) Finally, the model will be challenged to accurately represent three distinct behaviors of the DNA replication checkpoint during early development, providing a physiologic test case for the model and informing where additional data are needed.

因为细胞周期是所有真核生物生长发育的基础，也是细胞调控不当的基础

项目成果

A quantitative model of the effect of unreplicated DNA on cell cycle progression in frog egg extracts.

• DOI: 10.1016/j.jtbi.2009.05.018
• 发表时间: 2009-09-07
• 期刊: JOURNAL OF THEORETICAL BIOLOGY
• 影响因子: 2
• 作者: Zwolak, Jason;Adjerid, Nassiba;Bagci, Elife Z.;Tyson, John J.;Sible, Jill C.
• 通讯作者: Sible, Jill C.